Invasion of a pathogen (bacterium, virus, parasite or the like) into a host (human body or animal body) or generation of an endogenous inflammatory substance causes inflammatory reactions in which, for example, temporary contraction of arteriolae occurs at the site of invasion of the pathogen or the site of generation of the inflammatory substance, and expansion and hyperemia then occur, leading to local slowness of blood flow at the site of invasion of the pathogen or the site of generation of the inflammatory substance.
This causes adhesion of leukocytes to the vascular wall, and chemical mediators released from various immunocytes then act on the leukocytes to cause them to pass through the vascular wall by amoeboid movement and to allow their migration. Known examples of the chemical mediators include histamine, serotonin and lymphokines. Mast cells, which produce and release histamine and serotonin, are a type of lymphocytes that play a central role in the inflammatory reaction. Similarly to mast cells, macrophages also produce and release chemical mediators such as TNF.
The leukocytes whose migration was induced by the inflammatory reaction are attracted by the pathogen or the like, and this causes elimination (clearance) of the pathogen from the body by humoral immunity accompanied by antigen-antibody reaction and by cell-mediated immunity in which cytotoxic T cells and the like are involved, resulting in prevention of the spread of infection. Thus, the inflammatory reaction, and immune reactions that occur based on the inflammatory reaction, are extremely important for maintaining homeostasis of a living body.
On the other hand, the inflammatory reaction causes not only the biological defense described above, but also adverse signs/symptoms such as flare, fever, swelling, pain and dysfunction. Specific examples of such symptoms include allergic diseases, and various types of acute and chronic inflammations. Also in autoimmune diseases, in which the absence of immunological tolerance causes an autoimmune response, tissue injury occurs due to the inflammatory reaction.
That is, for prevention of a disease accompanied by the inflammatory reaction, it is important to kill the pathogen that causes the inflammatory reaction using antibiotics (antimicrobial agents), or to administer an agent that increases the immune function in the living body to eliminate the pathogen before an excessive inflammatory reaction occurs.
On the other hand, known examples of methods for amelioration or treatment of a disease accompanied by the inflammatory reaction include suppression of inflammation by administration of an agent (anti-inflammatory agent) that decreases excessively activated immune function by, for example, suppression of release of chemical mediators.
For example, Patent Document 1 discloses, as an immunostimulant, an activating agent for the function of dendritic cells, which are antigen-presenting cells responsible for activation of various immunocytes. More specifically, the agent comprises as an effective component(s) at least one branched chain amino acid selected from isoleucine, leucine and valine.
Patent Document 2 discloses, as an anti-inflammatory agent, an agent comprising the SPARC (Secreted protein which is acidic and rich in cystein) peptide and a pharmaceutical carrier.
It is known that a group of receptor molecules called MAIR (Myeloid Associated Ig like Receptors) are expressed on the cell membrane of myeloid (bone marrow) cells responsible for natural immunity (Non-patent Document 1). Among these, MAIR-I, which is also known as CD300a (also referred to as “LMIR1” or “CLM-8”), is expressed in macrophages, mast cells, granulocytes (neutrophils) and dendritic cells, and known to be an inhibitory receptor that associates with phosphatase via the ITIM (Immunoreceptor tyrosine-based inhibitory motif) sequence in the intracellular domain to transmit an inhibitory signal (Non-patent Document 2). However, the ligand for this receptor is unknown, and the receptor has been the so-called orphan receptor.
Atopic dermatitis is caused by entrance of an allergic substance (antigen) into the body followed by production of periostin due to stimulation by substances (interleukins 4 and 13) secreted from activated immunocytes, and then binding of the periostin to another protein “integrin” on the surface of keratinocytes in the skin, to cause inflammation.
The binding of periostin to integrin causes production of other inflammation-inducing substances, and the symptoms continue even in the absence of the antigen, resulting in chronicity. It has been shown, by an experiment using mice, that inhibition of binding of periostin to integrin using an inhibitor prevents occurrence of atopic dermatitis (Non-patent Document 3).
Although the major cause of atopic dermatitis has become evident, further elucidation of the pathology of atopic dermatitis, analysis of association of atopic dermatitis with other inflammatory diseases, and medicaments for atopic dermatitis that can be used in combination with the above inhibitor, are demanded.
Bronchial asthma is a respiratory disease in which bronchial inflammation triggered by an allergic reaction or infection with a bacterium or virus becomes chronic to thereby cause increased airway hyperresponsiveness and reversible airway narrowing, leading to symptoms such as attacks of wheezing, and cough. Further, bronchial asthma is said to be caused by the combination of airway hyperresponsiveness, allergic diathesis and environment. Recurrent symptoms such as wheezing, apnea, chest tightness and cough occur especially at night or in the early morning.
A number of cells and cellular components, especially mast cells, eosinophils, T-lymphocytes, macrophages, neutrophils and epithelial cells play roles in inflammation of the airway. Inflammation is associated with plasma exudation, edema, smooth muscle enlargement, mucus plugging, and epithelial changes. Further, inflammation causes associated increases in bronchial hyperresponsiveness to various stimuli.
Inflammation of the airway induces atrophy of airway smooth muscle, microvascular rupture and bronchial hyperresponsiveness. As the responsiveness of the airway increases, the symptoms become more severe and continuous, and daily variation of the pulmonary function increases. The mechanism of involvement of airway inflammation in the bronchial responsiveness is unknown, and tools useful for elucidation of the pathology of asthma, and medicaments and the like have been demanded.